1. Field of the Invention
The present invention relates to novel transient prodrug forms of thyrotropin-releasing hormone (TRH; thyroliberin)(pGlu-L-His-L-ProNH.sub.2), to methods for preparing the prodrug forms, to pharmaceutical compositions containing such prodrug forms, and to methods for using the prodrug forms.
For purposes of this specification, the term "prodrug" denotes a derivative of TRH which, when administered to warm-blooded animals, e.g. humans, is converted into the proven drug, i.e. TRH.
The term "transient" indicates that the conversion ot the prodrug forms proceeds in such a manner that the proven drug form (parent TRH) is released, and the remaining moieties splitt off remain nontoxic or are metabolized so that nontoxic metabolic products are produced.
These novel prodrugs forms of TRH are certain N-alkoxycarbonyl derivatives of TRH which possess a desirable high lipophilicity in comparison to the parent compound, TRH, and which are capable of protecting the parent compound, TRH, against enzymatic degradation or inactivation in vivo, e.g. in the blood.
2. Description of the Prior Art
TRH is the hypothalamic peptide that regulates the synthesis and secretion of thyrotropin from the anterior pituitary gland. Since the discovery of TRH in 1969, the peptide has been shown to have not only a variety of endocrine and central nervous system-related biological activity, but also potential as a drug in the management of various neurologic and neuropsychiatric disorders including depression and schizophrenia (see e.g. Metcalf, 1982; Jackson, 1982; Griffiths, 1986, 1987; Loosen, 1988). However, the clinical utility of TRH has been hampered by its rapid metabolism and clearance and its poor access to the brain (cf. e.g., Metcalf, 1982; Hichens, 1983; Griffiths, 1987). The poor penetration of TRH of the bloodbrain barrier is largely due to its very low lipophilicity (Banks & Kastin, 1985). Intravenous studies in rats and humans have shown that TRH has a plasma half-life of only 4-6 min (Bassin & Utiger, 1973; Morley et al., 1979; Duntas et al., 1988; Iversen, 1988). This short biological half-life is mainly due to rapid degradation of the tripeptide by enzymes endogenous to all body fluids and tissues, in particular by pyroglutamyl aminopeptidases including the so-called TRH-specific pyroglutamyl aminopeptidase serum enzyme (Bauer et al., 1981; Bauer, 1988; Wilk et al., 1988). The latter enzyme plays a major role in the rapid metabolism of TRH in human plasma (Bauer, 1988).
Accordingly, there is a need in the art to circumvent these problems of rapid enzymatic inactivation and poor lipophilicity of TRH.
It has now been found that it is possible to protect TRH against enzymatic inactivation and improve the lipophilicity by the prodrug approach according to the present invention.